Zopiclone, a medicine used for treatment of sleep disorder, was developed by RHONE-PONLENC RORER PHARMACEUTICAL COMPANY LTD, FRANCE in the mid-80s of the last century, and commercialized in more than 80 countries such as those countries in Europe under a trade name of IMOVANE®. The sales volume of this drug reached about 160 millions US$ in 1999, and had been used in China for nearly 10 years. Now, there are a lot of manufacturers producing it, including Shanghai Huashi Pharmaceutical Co., Ltd, Qilu Pharmaceutical Co., Ltd, and Guangdong Shunfeng Pharmaceutical Co., Ltd. The zopiclone is represented by a formula below:
S-zopiclone (Eszopiclone) is one chirally dextrorotatory monomer of zopiclone, having a chemical name of (+)-(S)-(4-methylpiperazine-1-carboxylate)(6-(5-chloropyridinyl -2-yl)-7-carbonyl-6,7-dihydro-5-H-pyrrolo[3,4-b]pyrazin-5-yl ester). Since 1998, it was developed by Sepracor Inc., and approved by FDA to sale in market in October 2004. However, there are a lot of severe side effects exhibited in the racemic zopiclone, including a bitter taste in mouth caused by secretion of the drug in saliva, dry mouth, drowsiness, morning fatigue, headache, dizziness and neuromotor function injury. Compared with the racemic zopiclone, the S-isomer thereof offers obvious advantages with fewer side effects. As revealed in a pharmacodynamics research, the dextrorotatory enantiomer of zopiclone significantly contributes to its short-term hypnotic effect, hence having a better effect than that of the racemic zopiclone. Meanwhile, S-zopiclone has been proved to show a low toxicity than that of the racemic zopiclone, as reported by a comparative acute toxicity research. In contrast to the racemic zopiclone, an administration of the S-isomer can have an effect of anti-anxiety without affecting sport coordination ability. Zopiclone is reported to be stereo-selective against a benzodiazepine receptor, wherein the S-isomer possesses approximately 50-fold higher binding affinity to the benzodiazepine receptor than that of the R-isomer.
It is well-known that a compound, such as a drug, can often exist in different crystalline forms, which is called polymorphism. Generally speaking, different crystalline forms of the same drug can have different physical properties and chemical stabilities. It is quite important to use a drug having a definite crystalline form as a bio-active component during a manufacture of pharmaceutical preparations, which will not only exert its therapeutical effects, but also effectively reduce its toxicity and side effects. Up to now, no descriptions about a definite crystalline form of S-zopiclone have been reported among those published preparative methods and applications of its composition.